Development of Small Molecule Antagonists of PAR-2 for treatment of asthma

摘要：目前对哮喘的治疗主要是为了通过以下方式减少病情恶化 直接治疗呼吸道炎症。虽然在部分患者中取得了成功，但哮喘 病情恶化仍然是发病率和死亡率的重要原因，并可导致呼吸道。 受伤、肺功能下降和死亡。更严重的哮喘患者的病情恶化是 尤其令人担忧的是，医疗保健成本和生产率损失在美国每年占210亿美元 年度医疗保健支出。因此，迫切需要开发新的治疗方法 用于治疗哮喘。蛋白酶激活受体-2(PAR-2)是一种G蛋白偶联受体 由引起哮喘的过敏原释放的丝氨酸蛋白酶激活的受体(例如德国 蟑螂、尘螨和交链格孢菌)，以及肥大细胞类胰蛋白酶， 人呼吸道胰酶，膜结合的TMPRSS2和中性粒细胞弹性蛋白酶。激活的PAR-2 通过过敏原或激动剂导致复杂的细胞信号(b-arrestin和Gaq-钙离子)， 有助于生理反应。使用转基因动物，我们已经展示了 PAR-2/b-arrestin信号会导致有害的结果(例如，细胞因子的产生， 白细胞浸润、上皮细胞增生、粘液分泌和呼吸道高反应性) 而PAR-2/Gaq-Ca~(2+)途径可能是有益的(例如，支气管松弛)。我们长达十年的 配基鉴定计划已经导致了一些最有效和最有选择性的PAR-2 激动剂和第一个完整的PAR-2拮抗剂C391。此外，我们已经证明了C391可以 在临床前模型中减少有害的交链孢霉诱导的哮喘指标。最近， 我们已经发现了几种新的小分子PAR-2拮抗剂，包括b-arrestin-2-受体拮抗剂。 选择性拮抗剂C781，是仅针对有害影响的有希望的候选药物 呼吸道中的PAR-2。我们的中心假设是b-arrestin选择性拮抗PAR-2 将减少过敏原诱导的哮喘指标，导致病情恶化。的第一个目标 这一阶段的STTR建议是为了展示第一个小分子偏向拮抗PAR-1。 2配体(C781)可有效限制临床前小鼠变应原诱导的哮喘指标 模特。第二个目标是修改C391和C781以用于肺特异性靶向，而 保留/改善其PAR-2拮抗功能。我们的公司PARMedics是 基于这样的原则，我们可以通过改进创建自定义修改 这类新型哮喘的药代动力学特性及稳定性研究 治疗学。

ABSTRACT: Current treatments for asthma largely are aimed at reducing exacerbations by directly treating airway inflammation. While successful in a subset of patients, asthma exacerbations remain a significant cause of morbidity and mortality and can result in airway injury, lung function decline and death. Exacerbations in more severe asthmatics are of particular concern, as health care costs and lost productivity account for $21 billion/year in US annual health care expenditures. Thus, there is a critical need to develop new therapies to be used in the treatment of asthma. Protease-activated receptor-2 (PAR-2) is a G-protein-coupled receptor activated by serine proteases released from asthma-inducing allergens (e.g. German cockroach, dust mites and the fungus Alternaria alternata), as well as by mast cell tryptase, human airway trypsin, membrane bound TMPRSS2 and neutrophil elastase. Activated of PAR-2 via allergens or agonists results in complex cellular signaling (b-arrestin and Gaq-Ca2+) that contribute to the physiological response. Using genetically modified animals, we have shown that PAR-2/b-arrestin signaling can lead to detrimental outcomes (e.g., cytokine production, leukocyte infiltration, epithelial hyperplasia, mucus secretion and airway hyperresponsivenes) while PAR-2/ Gaq-Ca2+ pathways can be beneficial (e.g., broncho-relaxation). Our decade-long ligand-identification program has resulted in some of the most potent and selective PAR-2 agonists and the first full PAR-2 antagonist, C391. Further, we have shown that C391 can reduce the detrimental A. alternata-induced asthma indicators in pre-clinical models. Recently, we have identified several novel small molecule PAR-2 antagonists, including the b-arrestin- selective antagonist C781 that is a promising candidate for targeting only the detrimental effects of PAR-2 in the airway. Our central hypothesis is that b-arrestin-selective antagonism of PAR-2 will reduce allergen-induced asthma indicators that lead to exacerbations. The first objective of this Phase I STTR proposal is to demonstrate the first small molecule biased antagonistic PAR- 2 ligand (C781) can effectively limit allergen-induced asthma indicators in a pre-clinical mouse model. The second objective is to modify C391 and C781 for pulmonary-specific targeting while retaining/improving on their PAR-2 antagonistic function. Our company, PARMedics, was founded on the principle that we can create custom modifications with improved pharmacokinetic properties and stability for the development of this new class of asthma therapeutics.